This project focuses on the molecular mechanisms that are activated by learning and support long-term memory formation in the brain. Many signaling pathways lie downstream of NMDA receptors (NMDARs), and several have been shown to contribute importantly to memory formation. These signaling events are believed to induce structural and functional synaptic modifications. However, the regulation of these signaling pathways is poorly understood. My laboratory believes that understanding the spatial and temporal signals that are engaged during the processes of learning will produce robust targets for the development of drugs that treat disorders of memory. SynGAP, which interacts with NMDARs, can regulate a broad spectrum of signaling pathways that lie downstream of these channels. This protein is unique because it is a core PSD component that also stimulates the dynamic regulation of small G-proteins. Interestingly, SynGAP has been shown to regulate both synapse structure and function, though the signaling pathways that mediate SynGAP-induced synaptic modifications are unknown. Recently, functional mutations in SynGAP were discovered in children with severe mental retardation, and these mutations are thought to cause non-syndromic and non-inherited forms of this disorder. We hypothesize that SynGAP modulates distinct signaling pathways in dendritic spines that maintains synapse structure and constrains AMPAR function. We believe that SynGAP lies downstream of learning-activated NMDARs, which would impart this protein with the unique ability to trigger rapid structural and functional plasticity at synapses. These synaptic changes would support the eventual consolidation of a newly acquired memory, and this hypothesis could explain how mutations in SynGAP cause cognitive impairments associated with mental retardation. To investigate this hypothesis, we propose to employ a novel approach to study AMPAR trafficking and synapse structure. We will combine SynGAP inhibitory peptides with two-photon imaging and electrophysiology to simultaneously assay changes in AMPAR function and corresponding changes to synapse structure. We will then attempt to dissociate signaling pathways that underlie each type of synaptic modification. Finally, we directly investigate the role of SynGAP in acquisition, consolidation and retrieval of hippocampus-dependent memories. This multifaceted approach will explain, at the molecular level, how a synaptic protein that regulates signaling dynamics, such as SynGAP, can support the formation of new memories in animals. Overall, we are optimistic that these studies will provide new insights into the molecular mechanisms of learning and memory, and could lead to potential new treatments for memory disorders and cognitive impairments. PUBLIC HEALTH RELEVANCE: Overall, this Project explores an innovative hypothesis aimed at evaluating and understanding if synaptic signaling pathways underlie the mechanisms of memory formation in the CNS. Understanding signaling pathways that are engaged by learning, such as those controlled by SynGAP, will give us novel insights into how protein function contributes to behavioral changes, and will hopefully lead to new treatment options and avenues for drug development for people with illnesses and conditions that cause memory dysfunction.